{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:11:38Z","timestamp":1780337498870,"version":"3.54.1"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":48,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clinical Research Priority Program CYTIMM-Z","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["320030_205097"],"award-info":[{"award-number":["320030_205097"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ITINERARE, a University Research Priority Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Tara Guetz Foundation and the University of Colorado School of Medicine, Department of Pediatrics","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Clinical Research Priority Program CGPD","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Cancer Research Center (CRC)","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:p>\n                    CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the\n                    <jats:italic>CD48<\/jats:italic>\n                    gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of ER stress signaling. Patient T cells displayed increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibited T cell lymphopenia, a restricted T cell receptor repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance, and pronounced inflammation. We conclude that identified variants compromise CD48 cell surface localization, impair T cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.\n                  <\/jats:p>","DOI":"10.1172\/jci191340","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T16:32:16Z","timestamp":1776270736000},"source":"Crossref","is-referenced-by-count":0,"title":["Variants in human CD48 lead to impaired T cell immunity and increased inflammation"],"prefix":"10.1172","volume":"136","author":[{"given":"Samantha","family":"Milanesi","sequence":"first","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Lorenzini","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Tintor","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Planas","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."},{"name":"Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Sabet","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."},{"name":"Children\u2019s Cancer Hospital Egypt 57357, Cairo, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Pediatric Immunology, University of Zurich, and the Children\u2019s Research Center, 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